Normally an individual produces 0.5 to 1 liter per day of saliva. Although varying greatly between individuals, on average 65 percent of saliva is submandibular, 23 percent from the parotids, 8 percent from the minor mucous, and 4 percent sublingual.
Xerostomia is a condition in which the salivary glands do not produce sufficient quantities of saliva. This causes discomfort which can in some cases be quite severe. Without saliva, the mouth burns and the throat and tongue can undergo radical changes. Teeth can decay rapidly and the tongue can become smooth, cracked and vulnerable to infection. There is often a loss of taste and, because saliva contains important digestive enzymes, there are often problems with digestion.
The persistence of a dry mouth at night can disturb sleep causing the individual suffering from it to waken frequently, even every hour. Furthermore periodontal disease and increased tooth decay as well as loss of teeth can be a result of xerostomia.
The mouth is one of the body areas most exposed to the external environment. Normally, mucous forms a continuous protective layer in the nose, mouth and throat. A patient suffering from xerostomia not only has decreased fluid in the mouth, but also an insufficient quantity of mucoproteins and mucopolysaccharides to hold fluid in contact with the cells and create a barrier to irritation and infection.
The onset of the effects of xerostomia is insidious with no clear line of demarcation when one has or has not the malady. Also different individuals may have different symptoms to a differing extent in a different succession. Dry mouth is the most common symptom. Alteration of taste sensation leads to change in the selection and perception of food. After alteration comes taste desensitation, which may lead to lack of any taste.
Sores on any of the mucous tissues of the oral area (tongue, gums, mouth, cheeks etc.), ulcerations, fissures, swellings, bleeding, coatings, even erosion of the tongue are all possible. With the decrease in saliva comes incomplete digestion, buildup of food, plaque, gingival hemorrhage, soreness at dental bridges, and extreme breath malodor. Also possible are swelling of various mouth tissues and possibly difficulty of speech. The lips may become desiccated or cracked. The rate of dental caries may increase dramatically.
It is estimated that several million individuals suffer from this condition nationwide. The actual number of individuals suffering from xerostomia is not known, however, because until recently there has been little acknowledgement of the prevalence or severity of the problem. It is estimated that about ten percent of the population over 50 years of age and 25 percent of the population over 65 years of age suffer from xerostomia. The majority of those affected are women.
Some direct primary causes of xerostomia are autoimmune diseases such as Sjogren's syndrome, medical irradiation, malnutrition, hormonal imbalance, arthritis and aging. When areas of the head or neck are medically irradiated by as little as 1000 rads per week, 85 percent of the patients suffer from xerostomia after six weeks and 95 percent after three months.
Radiation xerostomia onsets rapidly with a greater than 50 percent decrease in salivary flow after one week and a greater than 75 percent decline after six weeks of treatment. The xerostomia is progressive, persistent, and irreversible, reaching a greater than 95% reduction in saliva output three years after radiation. In patients where only part of the major salivary glands are in the path of the ionizing radiation, the non-exposed portion may undergo hyperplasia and partly compensate for the damaged acini. The most severe cases of xerostomia are caused by radiation therapy after head and neck surgery and by autoimmune diseases such as lupus, Sjogrens Syndrome, and rheumatoid arthritis. See, for example, P. C. Fox et al., J. Am. Dental Assoc. 110:519-525 (1985).
Decreased salivation during the post radiation therapy may have a significant impact on the patients quality of life, already impaired by the "bad news" of having cancer and numerous complications of chemo and radiotherapy such as nausea cephalalgia and dysphagia. As indicated above, saliva is important for the preservation of oral hard and soft tissues and for the normal execution of oral functions such as taste, swallowing and speech.
Secondarily, xerostomia is a side effect from the administration of over 400 drugs, including major antihypertensives, antidepressants, antispasmodics, diuretics, muscle relaxants, antipsychotics, appetite depressants, and therapeutics for Parkinson's disease.
In addition to radiation and chemotherapy induced salivary dysfunctions, a variety of other chronic inflammation and other immune disorders are also known which are characterized by diminished lacrimal and salivary gland secretions, e.g., Sjogren's syndrome. This is a chronic condition resulting in kerato-conjunctivitis sicca (KCS) and xerostomia.
The treatment of Sjogren's syndrome is aimed at symptomatic relief and limiting the damaging local effects of chronic xerostomia and xerophthalmia, which is a dryness of the conjunctiva and cornea. Ocular dryness responds to the use of artificial tears which may have to be applied as frequently as every 30 minutes. Slow release tear formulations are reported in the literature with limited success. Soft contact lenses are recommended to protect the cornea but increase the risk of infection. Saran wrap occlusion or diving goggles at night have been proposed to prevent tear evaporation. Xerostomia in Sjogren's patents is difficult to treat, but may temporarily relieved by frequent intake of water or artificial salivas, chewing gums, candies, etc.
Cases of xerostomia may vary from the mild, in which only slight dryness is experienced, to severe cases in which the patient will have serious problems with mastication, swallowing, digestion, speech, and the like. Breathing through the mouth may also induce xerostomia. Further, seasonal induced xerostomia is also experienced by some individuals. As noted in U.S. Pat. No. 4,438,100 to Balslev et al., other causes of xerostomia include the physiological (e.g., age, menopause, postoperative conditions, dehydration), as well as the psychic (nervousness).
Until recently, the treatments for xerostomia have had significant drawbacks. For example, symptoms of mild xerostomia can be somewhat alleviated by consumption of fluids, hard candy and throat lozenges. Food, in general, increases salivary flow. It has been known that the effects of secondary xerostomia may be broadly alleviated by sweet, sour, or bitter foods such as sweet candies, lemon drops, peppermint drops, chewing gum, and the like. Because of the susceptibility of xerostomia patients to tooth decay and gum disease, however, the increased sugar intake associated with conventional candy and lozenges is of real concern. In addition, fluids or candy are typically not effective with more severe cases of xerostomta, nor do they provide long-lasting relief with mild cases.
One general approach to xerostomia is the use of synthetic saliva. There are a number of artificial salivas on the market which contain alcohol, mineral oils, glycerins, and combinations of polyethylene glycols. There are many commercial brands, based on either pig mucin or carboxymethylcellulose (CMC), and including all the requisite electrolytes, buffer, and optional flavorants and/or sweeteners. The usual electrolytes are potassium, sodium, magnesium, calcium, chloride, bicarbonate, phosphate, and fluoride. Except for one Danish brand (Saliva-Orthana) and one Dutch experimental type based on mucin, most artificial salivas are based on CMC, such as those sold under the marks Orex.RTM. (Young Dental), Xero-Lube.RTM. (Scherer), Moi-Stir.RTM. (Kingswood Laboratories), and Salivart.RTM. (Westport Pharmaceuticals). Va-Oralube (First Texas Labs., Dallas) contains sorbitol and fluoride in addition to the appropriate electrolytes and CMC. Moi-Stir (Kingswood Co., Toronto) has a high sodium content and is mint flavored. Salube (Oraphorm Co., Australia) comes in small dropper bottles. Saliment (Richmond Pharm. Co., Ontario), also based on CMC, is lemon flavored. Xero-lube (Scherer Labs., Dallas, Tex.), Artisial (Jouvenal, Paris, France), and Glandosane (Fresenius, Bad Homburg West Germany) are available in ordinary spray bottles. Glycerins, hydroxyethylcellulose, and polyethylene oxides may also be found as bases for synthetic salivas. Many patients find, however, that such preparations are irritating or distasteful, and that their lubricating effect is of relatively short duration.
Another broad approach to alleviating the symptoms of xerostomia is to fit the mouth with a constant or controllable reservoir of synthetic saliva via a permanent or removable dental device. Palatal reservoirs require repeated refillings. A removable maxillary denture with reservoir rim is less cumbersome. It has several holes for filling with a syringe, drainage in use, and then washing after every meal. The removable denture with rim has space for about 3 ml of synthetic saliva. This denture, is expensive since custom-made, has an uncomfortable thickness, may hinder speech, and must be cleaned and refilled several times per day. J. A. Toljanic in Quintessence of Dental Technology, June 1985, pp. 355-358 and The Journal of Prosthetic Dentistry, volume 52, No. 4, pp. 540-544 shows pictures, gives directions, and has a bibliography on this subject. An informative background reference on xerostomia is P.C. Fox et al. (1985), J. Am. Dental Assoc. 110:519-525 (1985). There has also been some experimentation with parasympathomimetic drugs, i.e., drugs that mimic the action of the parasympathetic nervous system which controls salivation. There have been reported dosage control problems with these drugs, however, as well as significant side effects. These are generally administered in the form of tablets or capsules. Drugs which are known to be direct sialogogues include:
(a) pilocarpine compounds such as the hydrochloride, nitrate, or Jaborandi leaves or their extracts; PA1 (b) neostigmine and its bromide, distigmine bromide (Ubretid), pyridostigmine bromide (Mestinon); PA1 (c) nicotinic acid, nicotinamide (Nicobion 500), and benzopyrone (Venalot); and PA1 (d) carbachol (Doryl), potassium iodide, and anetholthrithion (Sulfarlem S 25) PA1 ascorbic acid (Vitamin C), citric acid tablets, malic acid, lemon glycerine swabs, and paraffin wax. PA1 (a) from about 2 to about 3 weight percent food-grade organic acidulent; PA1 (b) a food-grade sweetener benign to stomic microflora selected from the group consisting of a sugar, a synthetic sweetener, and a reduced, sugar-related compound, and PA1 (c) a saturated calciumphosphate solution.
Drugs known to be indirect sialogogues include:
The above information has been reviewed by Imfeld in volume 13, number 4, of Acta Parodontologics at pp. 1083/111-10996/124 (1984) and by Vissink et al. at volume 129, number 43 of Ned Tijdschrift Geneesked at pp. 2054-2057 (1985).
The following references relate to compositions and methods for treating xerostomia:
U.S. Pat. No. 4,438,100 to Balslev et al. discloses a viscous artificial saliva containing a mucine and an oxidizing bactericide.
U.S. Pat. No. 4,209,505 to Mikhail discloses a mouthwash for dry mouth relief, containing pilocarpine or a pilocarpine derivative. It is also noted therein notes that various types of diets have also been used (albeit unsuccessfully) in an attempt to alleviate xerostomia.
U.S. Pat. No. 4,151,270 to Ream et al. teaches a chewing gum composition formulated to stimulate salivation. The gum contains fructose and an organic acid such as adipic, ascorbic, citric, fumaric, lactic, malic or tartaric acids.
U.S. Pat. No. 4,938,963 discloses a method for treating xerostomia, comprising orally administering, to an affected individual, an amount of an eriodictyon fluid composition effective to alleviate the symptoms of dry mouth, the eriodictyon fluid composition comprising eriodictyon fluid extract and sweetener.
U.S. Pat. No. 4,917,674 discloses a medical device for the treatment of an individual suffering from xerostomia comprising two mouth moisturizing pads, each of which hold at least one sponge section wherein the sponge section is saturable with water for gradual dispensing of said water in the mouth.
U.S. Pat. No. 4,906,455 discloses a method for treating xerostomia wherein the patient chews, for a period of at least about 20 minutes, a gum containing a food-grade organic acid selected from the group consisting of adipic, fumaric, succinic, suberic, sebacic, azelic and pimelic acids.
U.S. Pat. No. 4,820,506 teaches a composition for promoting the production of human saliva consisting essentially of an aqueous liquid solution of water having dissolved therein:
The treatment of xerostomia with orally ingested pilocarpine is known in the art. Pilocarpine as 5 mg. capsules or tablets three to four times a day has been reported to show marked improvement in the salivary function along with manifestation of numerous side effects. Such treatment, however, presents a problem as pilocarpine is a highly potent parasympathomimetic drug which acts upon numerous parasympathomimetic responsive sites in the body. Because of this, the drug has many potential side effects and its therapeutic blood level concentration and toxic blood level concentration are not too far apart.
It is also known that pilocarpine can be used to treat xerophthalmia, a dryness of the conjunctiva and cornea. Further, pilocarpine has been used to alleviate excessive intraocular pressure. Unfortunately, the treatment of xerophthalmia and excessive intraocular pressure, by administration of pilocarpine to a patient in need of such treatment, is accompanied by the same problems as with respect to the treatment of xerostomia with orally ingested pilocarpine. Thus, a need has arisen for a method for treating xerophthalmia and excessive intraocular pressure, by administration of pilocarpine to a patient by a means that is efficacious, yet substantially free of the normally associated side-effects of pilocarpine therapy, such as sweating, flushing, stomach cramps.